Uses for Zocor

Prevention of Cardiovascular Events

ACC/AHA cholesterol management guideline recommends statins as first-line therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in adults; extensive evidence demonstrates that statins can substantially reduce ASCVD risk when used for secondary prevention or primary prevention (in high-risk patients).336337338350 Relative reduction in ASCVD risk is correlated with degree of LDL-cholesterol lowering; therefore, use maximum tolerated statin intensity to achieve optimum ASCVD benefits.350 According to ACC/AHA, simvastatin may be used for primary† or secondary prevention in adults when moderate-intensity statin therapy is indicated.350 (See Prevention of Cardiovascular Events under Dosage and Administration.)

Adjunct to nondrug therapies (i.e., lifestyle modifications350 ) in patients with CHD or CHD risk equivalents (e.g., diabetes mellitus, peripheral arterial disease, history of stroke or other cerebrovascular disease) to reduce the risk of total mortality by reducing CHD death, to reduce the risk of nonfatal MI and stroke, and to reduce the need for coronary and non-coronary revascularization procedures.1350 Unless contraindicated, statins are considered first-line therapy in patients 21–75 years of age with clinical ASCVD (i.e., acute coronary syndromes [ACS]; history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin).350

In the IMPROVE-IT study, addition of ezetimibe to simvastatin therapy further reduced LDL cholesterol and improved cardiovascular outcomes in post-ACS patients.309

Addition of niacin to statin-based therapy (i.e., simvastatin with or without ezetimibe) in patients with established cardiovascular disease not shown to provide incremental ASCVD risk reduction benefit beyond that provided by statin monotherapy.350354

In the SHARP study, fixed-combination preparation of simvastatin and ezetimibe was found to reduce risk of major vascular and atherosclerotic events in patients with chronic kidney disease.103308

Current recommendations from ACC/AHA regarding prevention of ASCVD and lifestyle modifications to reduce cardiovascular risk are available at or .352

May use in combination or fixed combination with ezetimibe for additive antilipemic effects.89103

Also used in combination with fenofibrate to decrease triglyceride concentrations and increase HDL-cholesterol concentrations in patients with mixed dyslipidemia and CHD (or CHD risk equivalents) who are on optimal statin therapy; however, no incremental benefit on cardiovascular morbidity and mortality beyond that provided by statin monotherapy.105353

Adjunct to nondrug therapies (e.g., dietary management) to decrease elevated serum total cholesterol, LDL-cholesterol, and apo B concentrations in the management of heterozygous familial hypercholesterolemia in boys and girls (≥1 year postmenarchal) 10–17 years of age who, despite an adequate trial of dietary management, have a serum LDL-cholesterol concentration of ≥190 mg/dL or a serum LDL-cholesterol concentration of ≥160 mg/dL and either a family history of premature cardiovascular disease or ≥2 other cardiovascular risk factors.1

Reduction of elevated serum total and LDL-cholesterol concentrations in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering therapies (e.g., plasma LDL-apheresis) or when such therapies are not available.1 May use in combination or fixed combination with ezetimibe for additive antilipemic effects.89103

Also has been used to reduce total and LDL-cholesterol concentrations in patients with hypercholesterolemia associated with or exacerbated by diabetes mellitus† (diabetic dyslipidemia),1355585974 cardiac†76 or renal† transplantation,77 or nephrotic syndrome†.6364

Zocor Dosage and Administration

General

Patients should be placed on a standard lipid-lowering diet before initiation of simvastatin therapy and should remain on this diet during treatment with the drug;1 in patients with CHD or CHD risk equivalents, initiate simvastatin simultaneously with dietary management.1

Monitoring during Antilipemic Therapy

Manufacturers recommend obtaining lipoprotein concentrations within 4 weeks following initiation of simvastatin monotherapy or 2 or more weeks after initiation or titration of therapy with the fixed-combination preparation (Vytorin), and then periodically thereafter.1103 ACC/AHA cholesterol management guideline recommends obtaining lipoprotein concentrations within 4–12 weeks following initiation of statin therapy (to assess response and adherence) and monitoring every 3–12 months thereafter as clinically indicated.350

Periodically reinforce adherence to lifestyle modifications.350

Administration

Oral Administration

Administer orally in the evening without regard to meals.1234

Simvastatin/ezetimibe fixed-combination preparation: Administer orally in the evening without regard to meals.103

Manufacturer and some clinicians recommend that patients avoid grapefruit juice.1103379 (See Specific Drugs and Foods under Interactions.) Because extent of the interaction may be influenced by quantity and timing of grapefruit juice consumption, other clinicians suggest that small amounts (e.g., 240 mL) may be acceptable.376378

Dosage

Pediatric Patients

Dyslipidemias

Oral

Children 10–17 years of age: Initially, 10 mg once daily.1

Adjust dosage at intervals of ≥4 weeks until the desired effect on lipoprotein concentrations is observed.1 Recommended dosage range is 10–40 mg daily.1

Secondary Prevention in Patients with Clinical ASCVD (i.e., ACS; history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin) (21–75 years of age)

Prescribing Limits

Pediatric Patients

Dyslipidemias

Oral

Children 10–17 years of age: Maximum 40 mg once daily.1

Adults

Prevention of Cardiovascular Events or Management of Dyslipidemias

Oral

Restrict use of 80-mg daily dosage to patients who have been receiving long-term therapy (e.g., ≥12 months) at this dosage without evidence of adverse muscular effects.1 (See Musculoskeletal Effects under Cautions.) In patients currently tolerating the 80-mg daily dosage who require therapy with an interacting drug (i.e., a drug with which concomitant use is contraindicated or is associated with a dose limit for simvastatin), switch to an alternative statin or statin-based regimen with less drug interaction potential.1

Simvastatin/ezetimibe fixed combination (Vytorin): Restrict use of simvastatin 80 mg/ezetimibe 10 mg dosage to patients who have been receiving long-term therapy (e.g., ≥12 months) at this dosage without evidence of adverse muscular effects.103 In patients currently tolerating the simvastatin 80 mg/ezetimibe 10 mg daily dosage who require therapy with an interacting drug (i.e., a drug with which concomitant use is contraindicated or is associated with a dose limit for simvastatin), switch to an alternative statin or statin-based regimen with less drug interaction potential.103

Special Populations

Hepatic Impairment

Use with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.1

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

Administer to women of childbearing age only when they are highly unlikely to conceive and have been informed of the potential hazards.1 If the patient becomes pregnant while taking the drug, immediately discontinue therapy and apprise the patient of the potential hazard to the fetus.1

Musculoskeletal Effects

Rhabdomyolysis (characterized by muscle pain or weakness with marked increases [>10 times the ULN] in serum CK concentrations and increases in Scr [usually accompanied by brown urine and urinary myoglobinuria])257 with or without acute renal failure secondary to myoglobinuria also reported; rare fatalities have occurred.1

Incidence of myopathy, including rhabdomyolysis, reportedly highest during first year and then notably decreased during subsequent years of treatment.1

Risk of myopathy is increased in patients receiving higher dosages of statins; risk also may be increased in geriatric patients (≥65 years of age), women, and patients with renal impairment or uncontrolled hypothyroidism.1

Certain drug or food interactions also may increase risk of myopathy and/or rhabdomyolysis.190919293103 (See Contraindications under Cautions and also see Interactions.)

Risk of myopathy, including rhabdomyolysis, is greater with 80-mg daily dosage compared with lower daily dosages or compared with other statins with similar or greater LDL-cholesterol lowering efficacy.1 Restrict use of 80-mg daily dosage.1 (See Prescribing Limits under Dosage and Administration.)

May consider periodic monitoring of CK concentrations when initiating therapy or increasing dosage; however, there is no assurance that such monitoring will prevent myopathy.1

If serious liver injury with clinical manifestations and/or hyperbilirubinemia or jaundice occurs, promptly interrupt simvastatin therapy.1 If an alternate etiology is not found, do not restart simvastatin.1

Endogenous Steroid Production

Small reductions from baseline in basal plasma testosterone concentrations observed in men; however, unlikely to be clinically important since no substantial effects on plasma gonadotropin concentrations, plasma testosterone response to human chorionic gonadotropin, spermatogenesis, or incidence of male adverse sexual effects observed.1

Effects on pituitary-gonadal axis in premenopausal women unknown.1

Cognitive Impairment

Generally nonserious and reversible, with variable times to symptom onset (1 day to years) and resolution (median of 3 weeks following discontinuance of therapy).1200 Not associated with fixed or progressive dementia (e.g., Alzheimer’s disease) or clinically important cognitive decline.200 Not associated with any specific statin, patient's age, statin dosage, or concomitant drug therapy.200

FDA states that cardiovascular benefits of statins outweigh the small increased risk of cognitive impairment.200

If patients present with confusion or memory impairment, ACC/AHA cholesterol management guideline recommends evaluating patient for statin as well as nonstatin causes (e.g., other drugs, systemic or neuropsychiatric causes).350

Role as Adjunct Therapy

Prior to institution of antilipemic therapy, vigorously attempt to control serum cholesterol by appropriate dietary regimens, weight reduction, exercise, and treatment of any underlying disorder that might be the cause of lipid abnormality.1

Risk of Cancer

Findings from the SEAS study suggested a possible increased risk of cancer with use of the fixed combination of simvastatin and ezetimibe.304306 The results of 2 subsequent randomized trials (SHARP and IMPROVE-IT) found no such association.305307308309 Based on currently available evidence, FDA has concluded that the fixed-combination preparation of ezetimibe and simvastatin (Vytorin) is not likely to increase the risk of cancer.307

Use of Fixed Combinations

When used in fixed combination with ezetimibe, consider the cautions, precautions, and contraindications associated with ezetimibe.103

Specific Populations

Pregnancy

Category X.1 (See Contraindications and also see Fetal/Neonatal Morbidity and Mortality, under Cautions.)

Lactation

Not known whether simvastatin is distributed into milk;1 however, a small amount of another statin is distributed into milk.1 Use is contraindicated in nursing women; women who require simvastatin therapy should not breast-feed their infants.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy of simvastatin not established in children <10 years of age or in premenarchal girls.1 Advise adolescent girls to use effective and appropriate contraceptive methods during therapy to reduce the likelihood of unintended pregnancy.1

Safety and efficacy of simvastatin in fixed combination with ezetimibe not established in children <10 years of age or in premenarchal girls.103 In patients 10–17 years of age, combination of simvastatin and ezetimibe associated with higher discontinuance rate and higher incidence of elevated aminotransferase or CK concentrations compared with simvastatin monotherapy.103

Geriatric Use

Simvastatin: No overall differences in safety or efficacy relative to younger adults.1 However, increased sensitivity cannot be ruled out; higher dosages (i.e., 80 mg daily) associated with increased risk of myopathy, including rhabdomyolysis, in patients ≥65 years of age.1 Use with caution, since age ≥65 years is a predisposing factor for myopathy.1 In patients >75 years of age, consider benefits, adverse effects, drug interactions, and patient preferences before initiating statin therapy.350

Simvastatin/ezetimibe fixed combination: No overall differences in safety or efficacy relative to younger patients; however, increased sensitivity cannot be ruled out.103 Use with caution, since age ≥65 years is a predisposing factor for myopathy.1

Hepatic Impairment

Use with caution in patients who consume substantial amounts of alcohol and/or have a history of liver disease.1

Renal Impairment

Because many patients who have developed rhabdomyolysis during simvastatin therapy have had complicated medical histories, including renal impairment secondary to chronic diabetes mellitus, closely monitor such patients.1

Use with caution in patients with severe renal impairment; dosage adjustments necessary in such patients.1 (See Renal Impairment under Dosage and Administration.)

In patients with moderate to severe renal impairment receiving simvastatin 20 mg/ezetimibe 10 mg in fixed combination, incidence of certain adverse effects (serious effects; those resulting in drug discontinuance; musculoskeletal effects, liver enzyme abnormalities, or incident cancer) was similar to that with placebo.103 Use higher dosages with caution and close monitoring in such patients, since renal impairment increases risk for myopathy.103 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Interactions for Zocor

Metabolized by CYP3A4; does not inhibit CYP3A4.1

Substrate of organic anion transport protein (OATP) 1B1.1

When used in fixed combination with ezetimibe, consider interactions associated with ezetimibe.103 No formal drug interaction studies to date with fixed-combination preparation other than that with extended-release niacin.103 (See Specific Drugs and Foods under Interactions.)

Concomitant use contraindicated; if short-term therapy with telithromycin is unavoidable, interrupt simvastatin therapy during anti-infective treatment1

Ticagrelor

Possible increased simvastatin plasma concentrations339

Some experts recommend limiting simvastatin dosage to 40 mg daily339

Warfarin

Possible increased PT;1339 bleeding observed with other statins1

Closely monitor PT until stabilized if simvastatin is initiated or dosage is adjusted in patients receiving warfarin; thereafter, monitor PT at intervals usually recommended for patients receiving warfarin1339

Advice to Patients

Importance of adhering to nondrug therapies and measures, including adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight.1350

Importance of obtaining fasting lipoprotein profile periodically.1

Risk of myopathy and/or rhabdomyolysis; risk increased with higher dosages (i.e., 80 mg daily) or when used concomitantly with certain other drugs or grapefruit juice.190919293 Importance of patients promptly reporting unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever, or if such manifestations persist after discontinuance of therapy.1

9. The Expert Panel. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Arch Intern Med. 1988; 148:36-69. [PubMed 3422148]

15. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993; 269:3015-23. [PubMed 8501844]

25. Expert Panel on Detection, Evaluation, and Treatment of high Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of high Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001; 285:2486-97. [PubMed 11368702]

26. The Expert Panel. Second Report of the Expert Panel on Detection, Evaluation , and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation. 1994; 89:1329-1445.

56. American Heart Association Committee to Design a Dietary Treatment of Hyperlipoproteinemia. Recommendations for treatment of hyperlipidemia in adults: a joint statement of the Nutrition Committee and the Council on Arteriosclerosis. Circulation. 1984; 69:1065-90A. [PubMed 6713610]

307. Food and Drug Administration. Follow-Up to the August 2008 Early Communication About an Ongoing Safety Review of Ezetimibe/Simvastatin (marketed as Vytorin), Simvastatin (marketed as Zocor) and Ezetimibe (marketed as Zetia) - FDA Investigates a Report from the SEAS Trial. Rockville, MD; 2009 Dec 21. Available from FDA website. Accessed 2008 Oct 9.